5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[33][34] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[33][35][36] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.[37][38]

Autoreceptors

5-HT1A receptors can be located on the cell body or soma, dendrites, axons, and both presynaptically and postsynaptically in nerve terminals or synapses. Those located on the soma and dendrites are called somatodendritic, and those located presynaptically in the synapse are aptly titled presynaptic. As a group, they are known as autoreceptors. Stimulation of 5-HT1A autoreceptors inhibits the release of serotonin in nerve terminals. For this reason, 5-HT1A receptor agonists tend to exert a biphasic mode of action; they decrease serotonin release and postsynaptic 5-HT1A receptor activity in low doses, and further decrease serotonin release but increase postsynaptic 5-HT1A receptor activity at moderate to high doses by directly stimulating the receptors in replacement of serotonin.

This autoreceptor-mediated inhibition of serotonin release has been postulated to be one of the reasons for the therapeutic lag that is commonly reported for most mainstream serotonergic antidepressants such as the SSRIs.[59] The autoreceptors must first densensitize before the concentration of extracellular serotonin in the synapse can become elevated appreciably.[59][60] Though the responsiveness of the autoreceptors is somewhat reduced with chronic treatment, they still remain effective at constraining large increases in extracellular serotonin concentrations.[59] For this reason, serotonin reuptake inhibitors that also have 5-HT1A receptor antagonistic or partial agonistic properties such as vilazodone and SB-649,915 are currently being investigated as novel antidepressants with a faster onset of action and greater efficacy than many of those currently available.[61]

Unlike most drugs that elevate extracellular serotonin levels like the SSRIs and MAOIs, SRAs such as fenfluramine and MDMA ("Ecstasy") fully bypass serotonin autoreceptors like 5-HT1A by forcing release to occur regardless of their inhibition.[62] This is why SRAs display immediate and full effects in contrast to drugs like the SSRIs, which require several weeks of chronic dosing before therapeutic benefits are seen, and also why SRAs are much stronger than SSRIs and related compounds in effect as they produce far more robust and balanced increases in extracellular serotonin concentrations.[63][64] For these reasons, selective serotonin releasing agents (SSRAs) including MDAI, MMAI, and 4-MTA have been proposed as novel antidepressants with an immediate onset of action and far greater efficacy in comparison to most current treatments.[63]

Sufficient doses of 5-HT1A receptor agonists themselves, like SRAs, are capable of fully bypassing the 5-HT1A autoreceptor-mediated inhibition of serotonin release and therefore decreased 5-HT1A postsynaptic receptor activation as well, by directly agonizing the postsynaptic receptors in lieu of serotonin. It is mentionable, however, that, unlike SRAs, 5-HT1A receptor agonists are incapable of bypassing the inhibitory effect of 5-HT1A autoreceptors located as heteroreceptors in non-serotonergicsynapses where 5-HT1A postsynaptic receptors are not present, which, instead of serotonin, modulate the release of other neurotransmitters such as dopamine or glutamate.